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From: Aaron Hill <>
Subject: [yDNAhgI] Preliminary Summary of New HIV-HG I Study
Date: Sun, 1 Feb 2009 02:43:09 +0000


Study Finds Infectious Disease-DNA Connection
Y Chromosome Haplogroup I Shows Greater Risk

Here is my preliminary summary of the key points in the new HIV-HG I study. Someone at NIH (National Institutes on Health) sent me a copy. They claim to have identified a genetic relationship between men of northern European descent, specifically those in haplogroup I, and HIV (“Association of Y chromosome haplogroup I with HIV progression, and HAART outcome”). This study is personal for me as my own yDNA (Y chromosome) is I1. The major mutation for this group is known as M253.

The study focused on haplogroups I, R and F* in Americans of European descent, and I, R and E in Americans with African ancestors. The researchers declared finding “a unique association between infectious disease and the Y chromosome haplogroup I.”

“Variation on the human Y chromosome is shaped by mutations ranging from single nucleotide changes to inversions, duplications, and deletions, causing larger structural changes that generate copy number variations ... Some of these [mutations] have been linked to diseases such as oligo/azospermia and gonadoblastoma, and shown to be represented frequently at certain Y haplogroups. However, no such mutation or structural change has been documented to be particularly associated with the Y-I haplogroup.”

The authors claimed the “study is the first to examine whether major Y haplogroups have an association with HIV infection and progression to AIDS” and that “the consistency of these results points to a significant role for the Y chromosome in human health ... An independent analysis of AIDS-related illnesses also suggests the increased risk of the Y-I haplogroup in all disease categories.”

“After some promising results were obtained for haplogroup I (Y-I), additional markers, M253, M227, P37, M26, and M223 were genotyped to define I1a*, I1a4, I1b*, I1b2, and I1c subhaplogroups (the corresponding YCC 2008 ... names are I1, I1b, I2a, I2a2 and I2b, respectively). The remaining Y-I haplogroup subjects who lacked the derived alleles at these markers were assigned into the I* (xI1a*, xI1a4, xI1b*, xI1b2, xI1c) paragroup.”

The report noted that a “faster disease progression in the Y-I haplogroup subjects was evident.” The “Cox model ... indicated that Y-I haplogroup subjects depleted CD4 cells more quickly ... and progressed to AIDS ... and death ... faster in the latter phase. The ... results were significant after multiple test corrections among the Y-I haplogroup individuals.”

“The Cox analyses suggested a relatively faster progression signal for the relatively common I1a* (I1) subhaplogroup compared to the other subhaplogroups. However, a Kaplan–Meier survival analysis did not find significant differences between the subhaplogroups indicating that the Y-I haplogroup as a whole best explains the acceleration to AIDS outcomes rather than any particular Y-I subhaplogroup.”

The study identified two possible explanations. A locus (or loci) on the Y chromosome could be responsible for the quicker onset of AIDS.

“As our results do not indicate an infection difference between the haplogroups, this locus might influence the AIDS progression pathway and lead to faster immunosuppression and AIDS outcomes.”

An alternative is the possibility of an autosomal locus linked with haplogroup I.

“In European Americans, many ARG polymorphisms [AIDS restriction genes] have been identified and found to influence HIV-1 infection.”

Yet, the researchers appeared to favor one theory, the Y chromosome.

“[O]utcomes observed in the Y-I haplogroup and the independence of the Y chromosome effect from that of the examined autosomal loci suggest a causal variant at a locus on the Y-I haplogroup ... So while a “winners curse” may be inflating these estimates, the consistency of these results points to a significant role for the Y chromosome in human health.”

“We also examined the frequency of Y chromosome haplogroups among subjects with different AIDS-defining illnesses. An analysis of haplogroup frequencies among cases and controls for AIDS-defining disease revealed a trend toward elevated frequency of Y-I haplogroup cases compared to [others] for all of the eight disease categories examined and a trend toward elevated malignancy development and Kaposi sarcoma for the Y-I haplogroup. These findings were consistent with a faster AIDS progression observed in the Y-I haplogroup subjects. A similar analysis of AIDS-defining disease as the first outcome showed seven of the eight disease categories with elevated Y-I haplogroup frequencies. However, neither the results nor the Cox models for specific disease outcomes were significant.”

The I subhaplogroups showed the same trend, but this was not due to a single subhaplogroup. Overall, more individuals within the I haplogroup had an increased chance of drug therapy (HAART) failure. In other words, medications, specifically antiretroviral, did not work at a greater rate than the general population.

“The early and initial stages of AIDS development indicated by the HIV-1 infection rate and plasma viral load levels, in the I, R, and F* haplogroups were not significantly different from each other. However, the Y-I haplogroup showed significantly longer HIV-1 viral suppression time and higher failure rate in HAART, outcomes that relate to later stages in AIDS progression. Moreover, the significant results after false-discovery-rate corrections for AIDS-1987, AIDS-related death, and HIV-1 viral suppression analyses suggest a potential biological basis for these observations. An independent analysis of AIDS-related illnesses also suggests the increased risk of the Y-I haplogroup in all disease categories.”

(Note that all emphasis in bold type and links are my own.)

-- Aaron
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