Genetic variants of the human serotonin transporter (SERT) may contribute to HPA axis dysregulation. SERT has two promoter region polymorphisms (5-HTTLPR: VNTR and SNP: rs25531), which may alter levels of SERT protein and its function. Combining these polymorphisms creates a functional polymorphism (FN) which may modulate mRNA expression. This study examines the relationship between these genetic variants and morning and evening salivary samples of both cortisol and dehydroepiandrosterone sulfate (DHEAS) concentrations in 269 African American (AA) adults. Resultant allele frequencies for the VNTR, SNP, and FN genotypes were 70&#x25; L (2&#x25; XLL), 84&#x25; A, and 54&#x25; LA (2&#x25; XLLA), respectively. The XLL genotype was associated with significantly higher concentrations of cortisol (&#x7e;3X) and DHEAS (&#x7e;2X) for both VNTR and FN polymorphisms. No significant differences were found for SNP genotypes. Conclusions were that persons with VNTR and FN XLL polymorphisms had significantly higher cortisol and DHEAS concentrations than other genotypes. AAs also appear to have a higher frequency of the rare XL allele than Caucasians. Whether the XLL genotype predisposes AAs to greater health challenges will require further research to determine the implications of these findings.

Carmen L. Contreras-Sesvold

Preetha Abraham

Joseph M. Devaney

Brennan T. Harmon

Patricia A. Deuster

The Association of 5-HTTLPR XLL Genotype with Higher Cortisol Levels in African Americans

The mutations in the <i>GJB2</i> gene are the most common cause of nonsyndromic hearing impairment and they are associated with the population&#x2019;s ethnic background. The p.Val27Ile is frequent in both Asia and America. In this retrospective study, we report the findings from the <i>GJB2</i> screening and the audiological exams conducted on 125 Mexican mestizo patients with non-syndromic hearing impairment; they were treated at the Instituto Nacional de Rehabilitacion in Mexico City. The most frequent audiometric findings were bilateral, symmetrical, and profound hearing impairment. The allele frequencies in the <i>GJB2</i> screening were p.Val27Ile 15&#x25;, other mutations 5&#x25;, and wild type 80&#x25;. We found no correlation between <i>GJB2</i> genotype and auditory phenotype. The high allele frequency of p.Val27Ile was a very interesting finding. Our research suggests that p.Val27Ile arose in an ancient common ancestor who lived in Altai Republic and then the polymorphism was brought to America by its first inhabitants, the Amerindians. These results enhance our understanding of the peopling of the America, which remains unresolved.

Guille Garc&#xed;a S&#xe1;nchez

Alfonso Alfaro-Rodr&#xed;guez

Adri&#xe1;n Poblano

Evidence for Central Asian Origin of the p.Val27Ile Variant in the <i>GJB2</i> Gene

Few studies focused on the association of<i> SORL1 </i>with the age at onset (AAO) of Alzheimer disease (AD). This study investigated the association of 43 SNPs in<i> SORL1</i> with the AAO of AD by using the Kaplan-Meier survival analysis and the Cox proportional hazards model in SAS version 9.2 and linear regression model in PLINK software (791 AD patients and 782 controls). Both logrank test and Cox regression model showed that five SNPs (rs1784934, rs676759, rs560573, rs593769, and rs11218313) were associated with the AAO of AD in the male sample, while one SNP (rs17125558) was associated with the AAO of AD in the female sample (<svg xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg" style="vertical-align:-0.1625795pt" id="M1" height="8.9689pt" version="1.1" viewBox="0 -8.80632 46.4857 8.9689" width="46.4857pt"><g transform="matrix(.0135,0,0,-0.0135,0,0)"><path id="g113-81" d="M600 480C600 590 528 650 384 650H143L137 622C222 614 225 607 210 531L130 127C113 41 106 36 23 28L17 0H294L300 28C204 36 195 42 212 127L243 284L314 263C327 263 339 263 352 264C465 271 600 337 600 480ZM508 481C508 351 402 304 329 304C289 304 265 311 250 317L295 559C302 594 310 606 323 611C335 616 350 619 367 619C455 619 508 573 508 481Z"></path><glyph.data ascent="3473" descent="-2876" horiz-adv-x="617" vert-adv-y="617"></glyph.data></g><g transform="matrix(.0135,0,0,-0.0135,12.15,0)"><path id="g117-91" d="M512 -3V55L134 254V256L512 456V514L75 281V230L512 -3Z"></path><glyph.data ascent="3473" descent="-2876" horiz-adv-x="587" vert-adv-y="587"></glyph.data></g><g transform="matrix(.0135,0,0,-0.0135,23.887,0)"><path id="g113-49" d="M241 635C89 635 35 457 35 312C35 153 89 -12 240 -12C390 -12 443 166 443 312C443 466 390 635 241 635ZM238 602C329 602 354 454 354 312C354 172 330 22 240 22C152 22 124 173 124 313S148 602 238 602Z"></path><glyph.data ascent="3473" descent="-2876" horiz-adv-x="480" vert-adv-y="480"></glyph.data></g><g transform="matrix(.0135,0,0,-0.0135,30.39,0)"><path id="g113-47" d="M113 -12C146 -12 170 11 170 46C170 78 146 103 114 103S58 78 58 46C58 11 82 -12 113 -12Z"></path><glyph.data ascent="3473" descent="-2876" horiz-adv-x="228" vert-adv-y="228"></glyph.data></g><g transform="matrix(.0135,0,0,-0.0135,33.48,0)"><use xlink:href="#g113-49"></use><glyph.data ascent="3473" descent="-2876" horiz-adv-x="480" vert-adv-y="480"></glyph.data></g><g transform="matrix(.0135,0,0,-0.0135,39.983,0)"><path id="g113-54" d="M153 550H386L412 615L406 623H120L82 318C104 327 142 338 184 338C294 338 347 275 347 187C347 112 305 39 221 39C160 39 119 71 97 89C88 97 80 96 71 90C59 80 50 67 49 57C48 45 52 36 66 23C80 9 123 -12 169 -12C221 -11 288 15 342 59C403 109 431 165 431 225C431 308 366 395 238 395C212 395 165 379 127 364L153 550Z"></path><glyph.data ascent="3473" descent="-2876" horiz-adv-x="480" vert-adv-y="480"></glyph.data></g></svg>). SNP rs560573, previously associated with the risk of late-onset AD, showed the most association with the AAO in the male sample (<svg xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg" style="vertical-align:-0.1625795pt" id="M2" height="8.9689pt" version="1.1" viewBox="0 -8.80632 59.4943 8.9689" width="59.4943pt"><g transform="matrix(.0135,0,0,-0.0135,0,0)"><use xlink:href="#g113-81"></use><glyph.data ascent="3473" descent="-2876" horiz-adv-x="617" vert-adv-y="617"></glyph.data></g><g transform="matrix(.0135,0,0,-0.0135,12.15,0)"><path id="g117-34" d="M535 323V373H52V323H535ZM535 138V188H52V138H535Z"></path><glyph.data ascent="3473" descent="-2876" horiz-adv-x="587" vert-adv-y="587"></glyph.data></g><g transform="matrix(.0135,0,0,-0.0135,23.887,0)"><use xlink:href="#g113-49"></use><glyph.data ascent="3473" descent="-2876" horiz-adv-x="480" vert-adv-y="480"></glyph.data></g><g transform="matrix(.0135,0,0,-0.0135,30.39,0)"><use xlink:href="#g113-47"></use><glyph.data ascent="3473" descent="-2876" horiz-adv-x="228" vert-adv-y="228"></glyph.data></g><g transform="matrix(.0135,0,0,-0.0135,33.48,0)"><use xlink:href="#g113-49"></use><glyph.data ascent="3473" descent="-2876" horiz-adv-x="480" vert-adv-y="480"></glyph.data></g><g transform="matrix(.0135,0,0,-0.0135,39.983,0)"><use xlink:href="#g113-49"></use><glyph.data ascent="3473" descent="-2876" horiz-adv-x="480" vert-adv-y="480"></glyph.data></g><g transform="matrix(.0135,0,0,-0.0135,46.486,0)"><path id="g113-56" d="M447 623H65C61 580 56 530 47 475H76C100 541 106 550 172 550H388C308 376 196 170 91 -1L98 -12L172 -2C268 204 360 408 455 611L447 623Z"></path><glyph.data ascent="3473" descent="-2876" horiz-adv-x="480" vert-adv-y="480"></glyph.data></g><g transform="matrix(.0135,0,0,-0.0135,52.991,0)"><use xlink:href="#g113-56"></use><glyph.data ascent="3473" descent="-2876" horiz-adv-x="480" vert-adv-y="480"></glyph.data></g></svg> for logrank test and <svg xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg" style="vertical-align:-0.1625795pt" id="M3" height="8.9689pt" version="1.1" viewBox="0 -8.80632 59.492 8.9689" width="59.492pt"><g transform="matrix(.0135,0,0,-0.0135,0,0)"><use xlink:href="#g113-81"></use><glyph.data ascent="3473" descent="-2876" horiz-adv-x="617" vert-adv-y="617"></glyph.data></g><g transform="matrix(.0135,0,0,-0.0135,12.15,0)"><use xlink:href="#g117-34"></use><glyph.data ascent="3473" descent="-2876" horiz-adv-x="587" vert-adv-y="587"></glyph.data></g><g transform="matrix(.0135,0,0,-0.0135,23.887,0)"><use xlink:href="#g113-49"></use><glyph.data ascent="3473" descent="-2876" horiz-adv-x="480" vert-adv-y="480"></glyph.data></g><g transform="matrix(.0135,0,0,-0.0135,30.39,0)"><use xlink:href="#g113-47"></use><glyph.data ascent="3473" descent="-2876" horiz-adv-x="228" vert-adv-y="228"></glyph.data></g><g transform="matrix(.0135,0,0,-0.0135,33.48,0)"><use xlink:href="#g113-49"></use><glyph.data ascent="3473" descent="-2876" horiz-adv-x="480" vert-adv-y="480"></glyph.data></g><g transform="matrix(.0135,0,0,-0.0135,39.983,0)"><path id="g113-50" d="M384 0V27C293 34 287 42 287 114V635C232 613 172 594 109 583V559L157 557C201 555 205 550 205 499V114C205 42 199 34 109 27V0H384Z"></path><glyph.data ascent="3473" descent="-2876" horiz-adv-x="480" vert-adv-y="480"></glyph.data></g><g transform="matrix(.0135,0,0,-0.0135,46.486,0)"><use xlink:href="#g113-50"></use><glyph.data ascent="3473" descent="-2876" horiz-adv-x="480" vert-adv-y="480"></glyph.data></g><g transform="matrix(.0135,0,0,-0.0135,52.989,0)"><use xlink:href="#g113-56"></use><glyph.data ascent="3473" descent="-2876" horiz-adv-x="480" vert-adv-y="480"></glyph.data></g></svg> in the Cox model). The mean AAO was approximately 2.5 years earlier in individuals who were homozygous for the minor allele compared with those who had at least one major allele. Linear regression model showed that rs2282649 and rs726601 were associated with AAO in the whole sample (<svg xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg" style="vertical-align:-0.1625795pt" id="M4" height="8.9689pt" version="1.1" viewBox="0 -8.80632 59.4945 8.9689" width="59.4945pt"><g transform="matrix(.0135,0,0,-0.0135,0,0)"><use xlink:href="#g113-81"></use><glyph.data ascent="3473" descent="-2876" horiz-adv-x="617" vert-adv-y="617"></glyph.data></g><g transform="matrix(.0135,0,0,-0.0135,12.15,0)"><use xlink:href="#g117-34"></use><glyph.data ascent="3473" descent="-2876" horiz-adv-x="587" vert-adv-y="587"></glyph.data></g><g transform="matrix(.0135,0,0,-0.0135,23.887,0)"><use xlink:href="#g113-49"></use><glyph.data ascent="3473" descent="-2876" horiz-adv-x="480" vert-adv-y="480"></glyph.data></g><g transform="matrix(.0135,0,0,-0.0135,30.39,0)"><use xlink:href="#g113-47"></use><glyph.data ascent="3473" descent="-2876" horiz-adv-x="228" vert-adv-y="228"></glyph.data></g><g transform="matrix(.0135,0,0,-0.0135,33.48,0)"><use xlink:href="#g113-49"></use><glyph.data ascent="3473" descent="-2876" horiz-adv-x="480" vert-adv-y="480"></glyph.data></g><g transform="matrix(.0135,0,0,-0.0135,39.983,0)"><path id="g113-52" d="M285 378C315 398 338 416 353 432C373 451 384 474 384 503C384 579 325 635 236 635H235C182 635 136 610 108 579L65 516L85 496C110 533 150 575 205 575C258 575 300 543 300 481C300 407 232 369 141 339L147 310C163 315 188 321 211 321C268 321 338 284 338 192C338 94 288 40 217 40C160 40 119 68 93 91C85 98 77 97 69 91C60 84 47 71 46 58C44 46 48 35 62 22C75 10 116 -12 162 -12C234 -12 424 62 424 224C424 297 373 359 285 376V378Z"></path><glyph.data ascent="3473" descent="-2876" horiz-adv-x="480" vert-adv-y="480"></glyph.data></g><g transform="matrix(.0135,0,0,-0.0135,46.486,0)"><use xlink:href="#g113-56"></use><glyph.data ascent="3473" descent="-2876" horiz-adv-x="480" vert-adv-y="480"></glyph.data></g><g transform="matrix(.0135,0,0,-0.0135,52.991,0)"><path id="g113-53" d="M456 178V225H360V632H320C217 496 115 347 20 206V178H280V106C280 40 276 34 189 27V0H445V27C364 34 360 39 360 106V178H456ZM280 225H82C149 335 214 431 278 520H280V225Z"></path><glyph.data ascent="3473" descent="-2876" horiz-adv-x="480" vert-adv-y="480"></glyph.data></g></svg> and 0.0367, resp.). These findings provide evidence of several genetic variants in<i> SORL1</i> influencing the AAO of AD.

Ke-Sheng Wang

Xuefeng Liu

Liang Wang

David Briones

Chun Xu

Genetic Variants in the <i>SORL1</i> Gene Are Associated with Age at Onset of Alzheimer Disease: A Survival Analysis

Polycystic ovary syndrome (PCOS) is the most common endocrinopathy affecting women of childbearing age causing not only reproductive but also metabolic anomalies. PCOS women present with ovulatory dysfunction, abnormal hormones, hyperandrogenemia, obesity, and hyperinsulinemia. It is a heterogeneous disorder which results from interaction of multiple genes along with environmental factors. Insulin resistance is a central key element contributing to PCOS pathogenesis and is further aggravated by obesity. Insulin regulates metabolic homeostasis and contributes to ovarian steroidogenesis. Candidate gene analyses have dissected genes related to insulin secretion and action for their association with PCOS susceptibility. Although a large number of genomic variants have been shown to be associated with PCOS, no single candidate gene has emerged as a convincing biomarker thus far. This may be attributed to large amount of heterogeneity observed in this disorder. This review presents an overview of the polymorphisms in genes related to insulin signaling and their association with PCOS and its related traits.

Nuzhat Shaikh

Roshan Dadachanji

Srabani Mukherjee

Genetic Markers of Polycystic Ovary Syndrome: Emphasis on Insulin Resistance

Several studies have demonstrated that chronic and low-grade inflammation is closely linked to type 2 diabetes mellitus. The associated mechanisms are related to synthesis and release of proinflammatory and anti-inflammatory cytokines, mainly by the adipose tissue. Moreover, there are evidences that cytokines and adhesion molecules are important for development of diabetic nephropathy. Among the cytokines associated with inflammatory responses in type 2 diabetes mellitus, the transforming growth factor-<i>&#x3B2;</i> (TGF-<i>&#x3B2;</i>) has been recognized as a central player in the diabetic nephropathy being involved in the development of glomerulosclerosis and interstitial fibrosis, as observed in the course of end-stage renal disease. Although TGF-<i>&#x3B2;</i>1 is classically an anti-inflammatory immune mediator it has been shown that in the presence of IL-6, which increases before the onset of T2D, TGF-<i>&#x3B2;</i>1 favors the differentiation of T helper 17 (Th17) cells that are activated in many pro-inflammatory conditions. Since TGF-<i>&#x3B2;</i>1 mRNA and consequently serum TGF-<i>&#x3B2;</i>1 levels are under genetic control, this review aims to discuss the relationship of TGF-<i>&#x3B2;</i>1 levels and polymorphisms in the development of nephropathy in type 2 diabetes mellitus.

Karina Braga Gomes

Kathryna Fontana Rodrigues

Ana Paula Fernandes

The Role of Transforming Growth Factor-Beta  in Diabetic Nephropathy

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International Journal of Medical Genetics

Table of Contents

Table of Contents

The Association of 5-HTTLPR XLL Genotype with Higher Cortisol Levels in African Americans

Evidence for Central Asian Origin of the p.Val27Ile Variant in the GJB2 Gene

Genetic Variants in the SORL1 Gene Are Associated with Age at Onset of Alzheimer Disease: A Survival Analysis

Genetic Markers of Polycystic Ovary Syndrome: Emphasis on Insulin Resistance

The Role of Transforming Growth Factor-Beta in Diabetic Nephropathy